Breast cancer is a major public health problem with high incidence and mortality rates. Inherited genetic factors have been shown to influence susceptibility to breast cancer and prognosis. The genetic basis to breast cancer may also differ by pathology subtypes. Our long-term objective is to understand how genetic variations modulate breast cancer risk and tumor characteristics. The nucleotide excision repair (NER) pathway and specializes in repairing a wide variety of DNA helix distortions. Significant decreases in DNA repair capacity (DRC) levels, which measures mostly the activity of the NER, have been observed in breast cancer cases from Puerto Rico when compared to non-cancer controls. In specific aim#1, we will identify copy number variants in the NER gene regions that are associated with breast cancer risk. We will first screening the NER pathway genes for the presence of CNVs using targeted array comparative hybridization (CGH). Next, we will assess the association of the identified CNVs in a breast cancer case-control population. In specific aim#2, we propose to determine the functional significance of the NER pathway CNVs on gene expression qualitatively (gene structure) or quantitatively (gene expression levels). We will perform targeted RNA-sequencing (RNA- Seq) on the NER gene pathway genes in which CNVs were identified. We will search for CNV associated gene expression changes, splice variants, and fusion transcripts. Specific aim#3 relies on our preliminary data showing that in Puerto Rican women, African ancestry is associated with higher risk of ER-PR- tumors. In this aim, we will identify the genomic regions underlying susceptibility to hormonal receptor-negative tumors in breast cancer patients using mapping by admixture linkage disequilibrium. This method takes advantage of the differences in the frequency of genetic variants between populations to uncover disease-causing genes. This application proposes an integrated and innovative strategy to improve our understanding of the role of genetics in breast cancer and it targets a Hispanic population, which is often underrepresented in genetic studies. With increasing discovery of common genetic variants that may cumulatively identify the extremes of the risk distribution, one can begin to envision personalized prevention of breast cancer by balancing the level of risk with an appropriate risk reduction intervention. The results from the proposed study can contribute importantly to this goal. The proposed project is expected to have a positive impact on the PI's career by providing the basis for the preparation of high quality manuscripts that will lead to R-type funding. Dr. Dutil is well trained in molecular genetics and i surrounded by a strong multidisciplinary team: Dr. Matta is an expert in DNA repair and will provide the study population of over 1,084 participants; Dr. Massey is an expert in bioinformatics applied to genomic data; Dr. Schabath is a cancer genetic epidemiologist; and Dr Ziv is a leader in the field of breast cancer admixture mapping.